Apparatus designed to modulate the neurovegetative system and integrate its action with that of the central nervous system; applications in the treatment of the vascular system and orthopaedic disorders

ABSTRACT

This invention relates to a new type of apparatus designed to modulate the neurovegetative system and integrate the neurovegetative action with that of the central nervous system. The method is not invasive, because it uses pulses transmitted through the skin; the intensity of the stimulus is controlled directly by the patient in order to achieve better integration with the central nervous system. This invention effectively treats vascular disorders resulting from obstruction of the arteries of the legs, heart and brain because it induces vasodilatation and increases blood flow and the production of new blood vessels. The method also improves lesions of the spinal column, especially those affecting the back and neck, and other orthopaedic disorders.

PURPOSE OF INVENTION

[0001] This invention relates to apparatus and an innovative methoddesigned to regulate the function of the neurovegetative system andintegrate it with that of the central nervous system. This effect isachieved by administering electrical pulses to the skin, the intensityof the pulses being controlled directly by the patient.

[0002] The new method induces vasodilatation, stimulates neoangiogenesisand increases blood flow. The regulation of the vascular flow obtainedwith the new technology allows treatment of vascular diseases involvingorganic obstruction of the arteries, which often affect the lower limbs,heart and brain. The new technology also allows effective treatment ofdisorders of the spinal column, especially the neck and the lumbosacralarea.

[0003] The same apparatus can be effectively used to treat many otherorthopaedic disorders, for example inflammation and proprioceptivesensory alterations caused by damage to the muscolar and articularsystem.

BASIS OF THE INVENTION

[0004] Atherosclerosis and thrombosis are frequent causes of arterialobstruction.

[0005] Atherosclerosis is responsible for most cases of arterialocclusion affecting the myocardium, brain and peripheral arteries.

[0006] Arterial obstruction or narrowing causes a reduction in bloodflow either during exercise or at rest. The clinical signs result fromischaemia. The atherosclerotic lesions which affect large and smallblood vessels in diabetics are very similar to those which appear innon-diabetics; however, they appear earlier, worsen more quickly and aremore frequent in the case of diabetics.

[0007] Distal arterial occlusion below the knee together withmicrovascular alterations and neurological lesions are responsible forgangrene. The symptoms are intermittent claudication and pain at restcaused by ischaemia. Diabetic foot, which is caused by a combination ofvasculopathy, neuropathy and infection, is one of the most dangerouscomplications of diabetes, and is the cause of most amputations.Amputation of the foot or leg is five times as frequent in diabetics asin non-diabetics. Angina and myocardial infarction are the most frequentcomplications of occlusion or stenosis of the coronary artery.

[0008] These local actions, together with those of the autonomic nervoussystem and the vascular system, cause vasoconstriction when activated,such as after exposure to cold; conversely, a reduction in these effectsresults in vasodilatation.

[0009] The development of collateral circulation which results fromstenosis or a major obstruction of the arteries influences the degree ofischaemia. Some collateral vessels are present in normal tissue, but donot dilate until arterial obstruction appears, while other capillariesdevelop in weeks or months. The adrenergic nerves, which are part of theautonomic nervous system, are responsible for vasoconstriction ordilatation of the collateral vessels in response to the increase inarterial pressure, with the result that the flow of blood to the tissueis improved.

[0010] Substances produced by the endothelial cells which induce newblood vessel formation (neoangiogenesis) and vasodilatation wererecently discovered. The production of VEGF (Vascular Endothelial GrowthFactor), which seems to be responsible for the majority of theangiogenic and vasodilatory effect that results from stenosis orarterial obstruction, appears to be particularly important.

[0011] Experiments with isolated animal muscles have demonstrated thatcontinuous electrical stimulation for 5 days (stimulation of 0.3 ms ofamplitude, frequency of 150 Hz and voltage of 0.1 V) increases VEGFproduction, the number of capillaries and the blood flow (Kanno S, OdamAbe M. Circulation 1999; 99, 2682-87).

[0012] Although the experiments described above seem to suggest thatelectrical stimulation of the muscles has beneficial effects on thecirculation, the problem remains of how to induce a prolongedstimulation on nerves and muscles in humans.

[0013] Patients suffering from acute ischaemia or initial infarctionpresent increased production of VEGF in the myocardium and in theendothelial cells of the capillaries and arterioles (Lee SH, Wolf PL,Escudero R, N. Engi. J. Med. 2000; 342, 626-33).

[0014] The revascularisation induced by a transmyocardial laser with theaim of reducing angina pain is accompanied by an increase in VEGF andangiogenesis (Horvath, Chiu E, Maun AC, Annals of Thoracic Surgery 1999;68, 825-29).

[0015] Modern technology offers some highly sophisticated instrumentswhich allow the use of new techniques such as transmyocardial laserrevascularisation, but the results are still limited. An electricalphoryngeal neuromuscolar stimulator is disclosed in WO 99/24111.

[0016] The treatment of peripheral vascular disease is usuallyunsatisfactory. Vasodilators have a modest effect, and sympathectomy isineffective. The injection of VEGF produced by GMO (Genetically ModifiedOrganisms) is not without side effects. The only therapeutic solution isvascular surgery.

[0017] In practice, no really effective system for the treatment ofperipheral vascular disorders has yet been found. Vasodilators give poorresults, treatment with VEGF based on recombinant DNA is not safeenough, and even surgery is just one of the various alternatives, whichhas not demonstrated any real efficacy.

[0018] The present invention proposes an apparatus for the treatment ofischaemic disease which can generate and apply a series of controlledpulses designed to stimulate the patient and elicit an effectiveresponse, which eliminates inflammation from the part of the bodytreated, activates the peripheral microcirculation and stimulates VEGFproduction.

[0019] The apparatus in accordance with the invention uses anon-invasive technique, because the stimulus is transmittedtranscutaneously by means of electrodes.

[0020] The signals emitted by the machine are sent to the vascularreceptors where they induce vasodilatation and stimulate VEGF release.

[0021] Using the apparatus in accordance with the invention, ischaemiacan be treated and ischaemic pain reduced.

[0022] The invention is based on a series of studies conducted by theapplicants which demonstrate that by applying a series of electricalpulses to the patient, a biochemical response can be induced which notonly eliminates inflammation from the part of the body treated andreduces or eliminates pain, but also has a rapid muscle-relaxant effect,and stimulates vasodilatation and VEGF production.

[0023] However, the apparatus must also detect the response of thetissues to electrical stimulation and vary the stimulation parameters toobtain the desired result.

[0024] For this purpose, the apparatus to which the invention relatesgenerates electrical pulses whose variables activate the patient'sneurophysiological control systems.

[0025] The pulse parameters are defined on the basis of the bioreactionof the tissues. The intensity of the pulse is directly regulated by thepatient, according to preset treatment programs.

[0026] After establishing experimentally that the apparatus inaccordance with the invention produces excellent results with musclerelaxation, the inventors formulated the hypothesis that the sameapparatus might effectively induce vasodilatation and stimulate VEGFproduction.

[0027] Subsequent experiments demonstrated that this hypothesis waswellfounded, and that the apparatus to which the invention relatesproduces the postulated results.

[0028] The apparatus according to the invention comprises:

[0029] means designed to generate electrical pulse series having a widthfrom 10 to 40 μsec and intensity from 100 to 170 μAmp, wherein eachpulse has a peak that has a width from 7 to 12 nanosec. and a voltage upto 220 Volts;

[0030] means designed to apply the said pulses to a patient through theepidermis;

[0031] means designed to evaluate the tissue reaction;

[0032] means designed to vary the said pulses on the basis of the tissuereaction detected;

[0033] at least one of which means can be controlled by thepatient/user.

[0034] The invention also provides a method of the treatment of vascularand/or muscle and/or tendon disorders, comprising:

[0035] a) applying to a patient in need thereof, a shies of electricalpulses having a width from 10 to 40 μsec and intensity from 100 to 170μAmp, wherein each pulse has a peak that has a width from 7 to 12nanosec. and a voltage up to 220 Volts trough electrodes located on theepidermis of the area to be treated;

[0036] b) detecting the tissue reaction after the application of thepulses;

[0037] c) modifying the width and intensity of the pulses in relation tothe tissue reaction detected in point b).

[0038] The invention also provides a method for increasing the VEGF in apatient in need thereof, comprising:

[0039] a) applying to a patient in need thereof, a shies of electricalpulses having a width from 10 to 40 μsec and intensity from 100 to170μAmp, wherein each pulse has a peak that has a width from 7 to 12nanosec. and a voltage up to 220 Volts trough electrodes located on theepidermis of the area to be treated;

[0040] b) detecting the tissue reaction after the application of thepulses;

[0041] c) modifying the width and intensity of the pulses in relation tothe tissue reaction detected in point b).

[0042] Advantages features of the apparatus of the invention are statedin the annexed dependent claims.

[0043] One embodiment of the apparatus is illustrated in the attachedfigures, in which:

[0044]FIG. 1 is a block diagram of the apparatus in accordance with theinvention

[0045]FIG. 2 is the circuit diagram of the forward/back selector switchin the circuit shown in FIG. 1

[0046]FIG. 3 is the circuit diagram of the selector switch-counter logicnetwork of the circuit shown in FIG. 1

[0047]FIG. 4 is a diagram of the up/down circuits, +DAC

[0048]FIG. 5 is the circuit diagram of the output stage of the circuitshown in FIG. 1

[0049]FIG. 6 is the circuit diagram of the timer in the circuit shown inFIG. 1

[0050]FIG. 7 is the circuit diagram of the automatic pulse train widthregulator in the circuit shown in FIG. 1

[0051]FIG. 8 is the circuit diagram of the frequency regulator and timerin the circuit shown in FIG. 1

[0052]FIG. 9 is the circuit diagram of the control activated by thepatient in the circuit shown in FIG. 1;

[0053]FIG. 10 shows the oscilloscopic trace of a pulse which shows apeak having a width of 10 nanosec.

[0054]FIG. 11 shows the waveform displayed by an oscilloscope, of thepulse of FIG. 10, over a total time of 100 nanosec.;

[0055]FIG. 12 is an expanded view of the peak of the pulse of FIG. 11.

[0056] The circuits illustrated in the figures do not require a moredetailed explanation because the information obtainable from thedrawings is sufficient to allow an expert in the field to implement theinvention.

[0057] The apparatus includes devices which generate and regulate aseries of electrical pulses that are sent to a pair of electrodes at theoutput, and is fitted with a control which allows the patient toregulate at least one of the control parameters of the said pulses,especially the voltage, according to preset treatment programscorrelating the detected bioreaction to the time, frequency and width ofthe electrical pulses.

[0058] The electrodes, one active and one passive (or reference)electrode, are applied in different positions, depending on the tissuetreated.

[0059] These regulations can be performed by means of an ordinarycontrol fitted with pushbuttons and/or potentiometers which is activatedby the patient.

[0060] The circuit shown in FIG. 2 allows forward/back regulation, inthat it allows the patient to select an increased or reduced voltage,while the circuit shown in FIG. 3 is a counting circuit which counts thenumber of steps set with the control, in order to calculate the extentof the variation to be imparted to the output voltage signal.

[0061] In particular, the amount of this voltage variation is between0.47 and 0.63 volts.

[0062] The digital count signal output from circuit 3 is then convertedinto an analog signal in the circuit shown in FIG. 4, where the pulsetrains are generated; they then pass to the output stage shown in FIG. 5after being suitably regulated by the circuits shown in FIGS. 6, 7 and8.

[0063] The circuits shown in FIGS. 6 and 7 regulate the duration (width)of the pulses and the increase in width between two successive pulsetrains.

[0064] The circuit shown in FIG. 8 is the timer which determines theduration of the pulse train, while FIG. 9 shows the circuit diagram ofthe control activated by the patient.

[0065] During the initial stage of the experiments, the apparatus wasregulated so as to generate a series of pulses with a voltage of approx.80 volts, the width of each pulse being selectable between 10 and 90microseconds, and the frequency being selectable between 1 and 999pulses a second.

[0066] The electrodes at the output of the apparatus were applied to theepidermis at the area to be treated, one to the motor point and theother to the muscle belly.

[0067] The tests were performed by effecting treatments of differentfrequencies ranging from 1 to 420 pulses a second, and different widths,ranging from 10 to 50 microseconds, for a total time of 10 to 15minutes.

[0068] 120 patients suffering from orthopaedic disorders whose maincomponent was local ischaemia or inflammation were treated.

[0069] The results demonstrated good vascularisation of the tissues, butthere was no significant improvement in the inflammation.

[0070] The pulses were checked with an oscilloscope, which showed thatthe pulse in contact with the skin underwent considerable deformation,and the patient developed evident tolerance after only 3 minutes.

[0071] During a second series of tests, the machine was set to vary thewidth of the pulses after each series of pulses applied in the samecycle, in order to prevent tolerance by the patient and deformation ofthe pulses.

[0072] 300 patients suffering from orthopaedic disorders complicated byinflammation and ischaemia were treated by applying several series ofpulses and increasing the pulse width from time to time during the sametreatment.

[0073] The results demonstrated that reduction of inflammation andimprovement in blood flow were associated with modulation of theneurovegetative nervous system.

[0074] A further test was then conducted with 120 patients sufferingfrom orthopaedic disorders associated with inflammation or deficiency ofthe local microcirculation.

[0075] The treatment comprised 12 ten-minute sessions in whichelectrodes were applied to the epidermis at a distance of approx. 10-15centimetres apart.

[0076] The patient could increase or decrease the voltage of the pulseduring stimulation with a remote control.

[0077] The variation in intensity of the pulse voluntarily decided on bythe patient and the variation in the physiological bioreaction time ormuscle relaxation times were observed simultaneously with a double-traceoscilloscope.

[0078] These first tests confirmed the inventor's intuition, namely thatthe application of series of electrical pulses under given voltage,frequency and width conditions could produce the desired results.

[0079] The following examples and tables show the results of further,more detailed tests.

EXAMPLE 1

[0080] Muscle relaxation (Tables 1a-d and 2) With the machine inaccordance with the invention, one electrode was applied to the motorpoint and one to the belly of the trapezius muscle, and pulse trainswere sent to the patient for 30 seconds at a voltage of approx. 180volts, with a frequency of one pulse a second and a width of 10microseconds.

[0081] During the second phase, lasting 5 seconds, the pulses wereapplied at the frequency of one a second, with a width of 20microseconds.

[0082] As the test continued, the parameters were varied from time totime as indicated in the annexed tables 1a to 1d until the musclereached spasm, then relaxed and remained in that condition.

[0083] As will be seen from the graph in Table 2, after approx. 12phases of treatment the muscle reached an almost permanent state ofrelaxation.

[0084] This relaxation corresponds to the maximum degree ofvascularisation and the maximum anti-inflammatory effect.

[0085] The anti-inflammatory treatment programme is shown in Table 3 andthe associated Graph 4.

[0086] Table 5 and the associated graph 6 show a treatment programme foractivation of the microcirculation.

[0087] The details set out above demonstrate that the apparatus inaccordance with the invention is able to relax the muscles, inducevasodilatation, increase the blood flow and stimulate new vesselproduction.

[0088] The technique is non-invasive because the signal is transmittedtranscutaneously through electrodes.

[0089] The signals emitted with this new technology are conducted by thesensory and proprioceptive fibres of the autonomic nervous system, andreach the vascular and muscle receptors through which vasodilatation andmuscle relaxation is produced; the blood flow is increased and VEGFrelease is stimulated.

[0090] The treatment combats ischaemia and reduces pain. The clinicalsymptoms of ischaemia, such as claudication due to contraction of thecalf, thigh or buttocks and pain at rest, rapidly regress, and thepatient walks normally.

[0091] Vasodilatation and increased blood flow take place in all partsof the body to which the treatment is applied. The effect islong-lasting; however, its duration depends on the degree of arterialobstruction and the time taken for collateral circulation to develop.Measurements taken with a laser doppler demonstrate significantincreases in blood flow in the treated areas.

[0092] The efficacy of the treatment is demonstrated by the followingexample.

EXAMPLE 2

[0093] 12 patients with distal arterial occlusion (7 with occlusion ofthe tibial artery and 5 with occlusion of the femoral artery) werestudied before, during and after stimulation with the new technology.

[0094] The VEGF (pg/ml) was assayed at the times shown in FIG. 10.

[0095] As will be seen, an increase in VEGF was already evident 2-3minutes after the start of the stimulus; it peaked after 5 mins (theincrease was approx. 50%), and returned to normal after 15 mins.

[0096] Further tests confirmed that the best results can be obtainedwith series of pulses having a width from 10 to 40 μsec. and anintensity from 100 to 170 μAmp., with a peak having a width from 7 to 12nanosec. and a voltage up to 220 Volts.

[0097] The waveform of a pulse of this kind, as displayed by anoscilloscope, is shown in FIGS. 10-12.

[0098] These data demonstrate for the first time that the application ofthe invention is able to increase VEGF, the most potent specificendogenous angiogenic factor identified to date. Increased VEGFproduction was also accompanied by vasodilatation. By contrast with whathappens in laboratory animals subjected to a direct stimulus on theisolated muscle and nerve, this method enables the stimulus to beinduced through the skin with electrodes. The time taken to stimulateVEGF is a few minutes, whereas the electrical stimulation used inanimals takes days to achieve the same result. In the case of severestenosis or arterial obstruction, recurrence of the ischaemia symptomsafter suspension of the treatment is often due to a deficiency in thedevelopment of collateral circulation. In this case the treatment mustbe continued or an arterial bypass performed, which may be followed bynew treatment to ensure complete healing of the tissues.

[0099] Maintenance of a high blood flow in the treated tissues increasesthe trophism of the tissue, prevents necrosis and heals ulcers.

[0100] The application of this invention to specific parts of the bodyrather than directly to the heart induces coronary vasodilatation andincreases VEGF production in the coronary sinus.

[0101] This effect has been observed in 3 patients who underwent cardiaccatheterisation, from whom blood samples were taken at the same time toassay the cardiac VEGF.

[0102] The treatment can also be applied to lesions of the spinal columnand pain syndromes of the back and neck.

[0103] The spinal column, together with the spinal cord, nerve roots,spinal ligaments and paraspinal muscles are the sites of some of themost frequent disorders to which human beings are liable. The cervicaland lumbar pain which originates in these structures affects nearlyeveryone sooner or later. This disorder, together with alcoholism, isone of the major causes of absenteeism.

[0104] The most important symptom of lesions of the spinal column andthe various structures that compose it is pain, which may be local ormuscle-related. Pain is caused by irritation of the nerve ending at thesite of the pathological process. Treatment of patients with cervicaland back pain is very difficult, and often ineffective. Rest, combinedwith analgesics, is currently considered to be the best treatment.Physiotherapy is performed with the aim of strengthening theparavertebral muscles to prevent painful relapses. Neck manipulation ispotentially dangerous. This invention provides an innovative approach tothe treatment of lesions of the spinal column.

[0105] As mentioned, this new technology acts through the autonomicnervous system, targeting the structures of the spinal column which aremost often affected by painful disorders, such as the ligaments,periosteum and paravertebral muscles, by acting on the muscle spindles,the Golgi tendon organs and the joint proprioceptors. Its action isfollowed by a reduction in oedema, inflammation and pain.

[0106] This treatment has been tested on some 200 patients sufferingfrom cervical or lumbar pain.

[0107] Most of the patients felt better within a few days (3-10). 60 ofthem had a slipped disc; 10 of them had already been operated on forslipped disc but still felt pain. The treatment was effective in 92% ofcases. 90% of the patients suffering from slipped disc did not need anoperation because the compression or inflammation symptoms of the nerveroot were eliminated by the treatment.

[0108] The results obtained with this method demonstrate that thetechnique has multiple effects on mechanical lesions of the spinalcolumn and their complications:

[0109] it eliminates pain and returns the proprioceptive sensitivity tonormal

[0110] it restores normal muscle contractility

[0111] it eliminates inflammation.

[0112] The same technology has been tested in other disorders.

[0113] For example, the invention has been successfully tested in thetreatment of numerous other disorders such as cervical, back, hip, thighand knee pain, knee instability, Achilles tendinitis, calcaneal spur,metatarsalgia, and shoulder, elbow, wrist and hand disorders.

[0114] In conclusion, the new treatment improves the quality of life andreduces one of the most frequent causes of absenteeism.

1. Apparatus for the treatment of vascular and/or muscle and/or tendondisorders and/or to increase the production of VEGF, comprising: meansdesigned to generate electrical pulse series having a width from 10 to40 μsec and intensity from 100 to 170 μAmp, wherein each pulse has apeak that has a width from 7 to 12 nanosec. and a voltage up to 220Volts; means designed to apply the said pulses to a patient through theepidermis; means designed to evaluate the tissue reaction; meansdesigned to vary the said pulses on the basis of the tissue reactiondetected; at least one of which means can be controlled by thepatient/user.
 2. Apparatus for the treatment of vascular and/or muscleand/or tendon disorders as claimed in claim
 1. 3. Apparatus as claimedin each of the preceding claims, wherein the voltage of the pulsesapplied is controlled by the patient/user by suitable means. 4.Apparatus as claimed in each of the preceding claims, characterised inthat it includes a pair of electrodes designed to transmit the saidpulses, one of which can be applied to the motor point and the other tothe muscle belly in the area to be treated.
 5. Apparatus as claimed ineach of the preceding claims, characterised in that the said meansdesigned to transmit the said pulses include devices able to vary thevoltage, amplitude and frequency of the said pulses.
 6. Apparatus asclaimed in each of the preceding claims, characterised in that itincludes means designed to regulate the amplitude and frequency of thepulses, which said means are activated directly by the patient. 7.Apparatus for the treatment of muscle contraction as claimed in claim 1,characterised in that it includes a pair of electrodes designed totransmit the said pulses, one of which can be applied to the motor pointand the other to the muscle belly in the area to be treated. 8.Apparatus for anti-inflammatory treatment as claimed in claim 1,characterised in that it includes an active electrode designed to beapplied at the site of inflammation, and a passive electrode external tothe said site.
 9. Apparatus for the treatment of vascular disorders asclaimed in claim 1, characterised in that it includes an activeelectrode designed to be applied upstream of the occlusion and a passiveelectrode designed to be applied downstream thereof.
 10. Apparatus forthe activation of the microcirculation as claimed in claim 1,characterised in that it includes an active electrode designed to beapplied at the ischaemic site and a passive electrode designed to beapplied close to the venous plexus.
 11. Apparatus as claimed in claim 1,characterised in that it includes means designed to vary the voltage ofthe pulses applied, with variable increments between 0.47 V and 0.63 Vfor each step of the up/down circuit.
 12. Apparatus as claimed in claim1, characterised in that it includes means designed to vary the numberof pulses applied between 1 and 420 Hz/second.
 13. Apparatus as claimedin claim 1, characterised in that it includes means designed to vary thewidth of the pulses between 10 and 50 μsec.
 14. A method of thetreatment of vascular and/or muscle and/or tendon disorders, comprising:a) applying to a patient in need thereof, a shies of electrical pulseshaving a width from 10 to 40 μsec and intensity from 100 to 170 μAmp,wherein each pulse has a peak that has a width from 7 to 12 nanosec. anda voltage up to 220 Volts trough electrodes located on the epidermis ofthe area to be treated; b) detecting the tissue reaction after theapplication of the pulses; c) modifying the width and intensity of thepulses in relation to the tissue reaction detected in point b).
 15. Amethod according to claim 14 wherein the pulses are modified accordingto preset treatment programs correlating the detected bioreaction to thetime, frequency and width of the electrical pulses.
 16. A method forincreasing the VEGF in a patient in need thereof, comprising: a)applying to a patient in need thereof, a shies of electrical pulseshaving a width from 10 to 40 μsec and intensity from 100 to 170 μAmp,wherein each pulse has a peak that has a width from 7 to 12 nanosec. anda voltage up to 220 Volts trough electrodes located on the epidermis ofthe area to be treated; b) detecting the tissue reaction after theapplication of the pulses; c) modifying the width and intensity of thepulses in relation to the tissue reaction detected in point b).